Armando J. Parodi, Ph.D.  Career Investigator of the National Research Council (CONICET, Argentina) Send Mail

Career Investigator of the National Research Council (CONICET, Argentina)
Former Professor of Biochemistry, School of Exact and Natural Sciences, University of Buenos Aires.
International Research Scholar, Howard Hughes Medical Institute
Member, National Academy of Exact, Physical and Natural Sciences (Argentina)
Member, National Academy of Sciences (Argentina)
Foreign Member, Brazilian Academy of Sciences
Foreign Associate, National Academy of Sciences (USA)
Member, American Academy of Microbiology

M.Sc. (1965), School of Exact and Natural Sciences, University of Buenos Aires. Discipline: Organic Chemistry
Ph. D. (1970), School of Exact and Natural Sciences, University of Buenos Aires. Discipline: Biochemistry
Post-doctoral John. S. Guggenheim Memorial Fellow (1972-1974) Département de Biologie Moléculaire, Institut Pasteur, Paris. Discipline: Molecular Virology

LAB MEMBERS

Dra. Olga A. Castro, Career Investigator (CONICET)
Dra. Cecilia D´Alessio, Career Investigator (CONICET)
Dr. Carlos A. Labriola, Career Investigator (CONICET)
Dr. Ana María Villamil Giraldo, Post-doctoral Fellow (CONICET)
Iván D. Stigliano, Graduate Student (Doctoral Fellow of ANPCYT)

Research performed at the Laboratory of Glycobiology is related to certain aspects of the etiology of the so called “conformational diseases”, that is diseases caused by proteins unable to acquire their native tertiary or quaternary structures. Our studies specifically deal with the folding process of a particular type of proteins, those having oligosaccharides covalently attached to their polypeptide chains (glycoproteins).
Protein N-glycosylation starts in the lumen of the endoplasmic reticulum by the transfer of an oligosaccharide from a lipid derivative to asparagine residues in nascent polypeptides. Almost all proteins following the secretory pathway are thus post-translationally modified. Furthermore, recently formed glycoproteins acquire their tertiary and quaternary definitive structures in the endoplasmic reticulum. Glycoprotein monomers not yet displaying those structures or multimeric complexes not yet having the full complement of subunits are initially retained in that subcellular location and only those species in which the inability to acquire the native tertiary or quaternary structures is permanent are transported to the cytosol to be degraded in the proteasomes. Several components are involved in this so called “quality control” of glycoprotein folding: a glucosyltransferase, that plays a key role as it only glucosylates glycoproteins not displaying their native tertiary or quaternary structures, a glucosidase, that removes the residue added by the glucosyltransferase, and two lectins, calnexin and calreticulin, that specifically recognize the structure created upon glucose addition. It has been proposed that the signal indicating cells that glycoproteins are permanently misfolded and that they have to be driven to proteasomes could an oligosaccharide generated by an endoplasmic reticulum a-mannosidase. This oligosaccharide would be recognized and driven to degradation by an a-mannosidase homologue called EDEM, not having enzymatic activity but putatively behaving as a lectin.  We are currently studying the structure and mode of action of the enzyme that transfers the oligosaccharide to nascent polypeptide chains (the oligosaccharyltransferase) and of several quality control components (glucosyltransferase, glucosidase) as well as the protein determinants recognized by the glucosyltransferase in glycoproteins not displaying their native tertiary or quaternary structures. We are further studying also the mechanism of recognition and transport to degradation of glycoproteins irreparably misfolded or unable to form complete multimeric complexes. As UDP-Glc is the donor substrate used by the glucosyltransferase in the endoplasmic reticulum lumen, we are studying additionally the mechanism as well as its regulation, by which this nucleotide sugar is transported from the cytosol, where it is synthesized, into the lumen.

It is worth mentioning that in certain cases glycoproteins displaying localized structural distortions not affecting their biological activities are retained and further degraded in the endoplasmic reticulum. Further knowledge of the quality control mechanism might conceivably provide means for forcing those glycoproteins to successfully overcome the control, thus allowing them to reach their normal destinations.

Castro, O. A., Movsichoff, F. and Parodi, A. J. (2006). Preferential Transfer of the Complete Glycan is Determined by the Oligosaccharyltransferase Complex and not by the Catalytic Subunit. Proceedings of the National Academy of Sciences (USA), 103, 14756-14760.
D´Alessio, C., Caramelo, J. J and Parodi, A. J. (2005). Absence of Nucleoside Diphosphatase Activities in the Yeast Secretory Pathway Does Not Abolish Nucleotide Sugar-Dependent Protein Glycosylation. The Journal of Biological Chemistry, 280, 40417-40427.
Movsichoff, F., Castro, O. A. and Parodi, A. J. (2005). Characterization of Schizosaccharomyces pombe ER a-mannosidase. A re-evaluation of the role of the enzyme on ER-associated degradation. Molecular Biology of the Cell, 16, 4714-4724.
Keith, N., Parodi, A. J. and Caramelo, J. J. (2005). Glycoprotein Tertiary and Quarternary Structures are Monitored by the Same Quality Control Mechanism.The Journal of Biological Chemistry, 280, 18138-18141.
Caramelo, J. J., Castro, O. A,, de Prat-Gay, G. and Parodi, A. J. (2004). The Endoplasmic Reticulum Glucosyltransferase Recognizes Nearly Native Glycoprotein Folding Intermediates. The Journal of Biological Chemistry, 279, 46280-46285.
Caramelo, J. J., Castro, O. A., Alonso, L. G., de Prat-Gay, G. and Parodi, A. J. (2003). UDP-Glc:glycoprotein Glucosyltransferase Recognizes Structured and Solvent Accessible Hydrophobic Patches in Molten Globule-like Folding Intermediates.
Proceedings of the National Academy of Sciences, USA, 100, 86-91.
Trombetta, E. S. and Parodi, A. J. (2003). Quality control and protein folding in the secretory pathway. Annual Review of Cell and Developmental Biology. 19, 649-676.

National Institutes of Health (USA) (RO1 GM44500, 1990-2008)
International Research Scholar, Howard Hughes Medical Institute (1997-2011)
National Agency for the Promotion of Science and Technology (ANPCYT) (PICT 2003 and PICT 2005)